The long-term objective of this project is to develop antibody-based medications for the treatment of medical problems caused by abuse of methamphetamine ((+)METH)), amphetamine and ecstasy. Abuse of these chemicals can lead to disruption of families, psychosis, cardiovascular problems, and death. It is envisioned that these new medications could be used for treating a range of medical problems associated with synthetic stimulant abuse (e.g., drug overdose, addiction). Although medicines are sorely needed, these drugs and their active metabolites present a challenging problem for the development of effective medications. The experiments in this proposal are designed to address these problems by discovering anti-drug monoclonal antibodies (mAb, both mouse and human) that recognize and neutralize the in vivo effects of these dangerous chemicals. The selection criteria for the mAb medications will include high affinity drug binding, refined specificity for METH-like drugs and metabolites, and in vivo testing for their ability to prevent brain penetration of these chemicals. In complementary studies, the best mAb prototypes will be used to generate single chain antibodies (scFv) by linking the heavy and light chain variable region sequences through a spacer group. Research with these smaller binding proteins will include two separate areas. First, in vitro protein translation techniques will be used to screen for scFv with improved affinity and specificity. Second, the scFv will be chemically modified with poly(ethylene glycol) to allow control of the pharmacokinetic properties. Since scFv are much smaller than intact mAb and are engineered as a single gene product, they could eventually lead to less expensive medications. Through careful design of METH-like haptens, generation of mouse and human mAb, and advanced molecular engineering technology, this research program will produce novel protein-based medications with optimal immunological and pharmacological properties. Because all of these medications can neutralize drug effects without entering the brain, they offer an innovative and unique approach to treating medical problems resulting from stimulant abuse.